NM_018136.5:c.8820+7C>G

Variant names:

• chr1-197100424-G-C
• rs115045814
• NM_018136.5:c.8820+7C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.8820+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,462,178 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (14 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001279
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.20
• Publications: 2 publications found

Genes affected

ASPM (HGNC:19048): (assembly factor for spindle microtubules) This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]

ASPM Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-197100424-G-C is Benign according to our data. Variant chr1-197100424-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00793 (1203/151730) while in subpopulation AFR AF = 0.0274 (1136/41450). AF 95% confidence interval is 0.0261. There are 13 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.8820+7C>G		splice_region intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.4066-4260C>G		intron	N/A	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.8820+7C>G		splice_region intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-4260C>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-4260C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1199 AN: 151612 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00317

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00251 AC: 446 AN: 177432 AF XY: 0.00191

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000916 AC: 1200 AN: 1310448 Hom.: 14 Cov.: 23 AF XY: 0.000844 AC XY: 550 AN XY: 651662

African (AFR) AF: 0.0297 AC: 836 AN: 28104

American (AMR) AF: 0.00273 AC: 85 AN: 31178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23002

East Asian (EAS) AF: 0.00 AC: 0 AN: 36728

South Asian (SAS) AF: 0.0000687 AC: 5 AN: 72818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49996

Middle Eastern (MID) AF: 0.00180 AC: 7 AN: 3880

European-Non Finnish (NFE) AF: 0.000153 AC: 155 AN: 1010670

Other (OTH) AF: 0.00207 AC: 112 AN: 54072

GnomAD4 genome AF: 0.00793 AC: 1203 AN: 151730 Hom.: 13 Cov.: 32 AF XY: 0.00773 AC XY: 573 AN XY: 74158

African (AFR) AF: 0.0274 AC: 1136 AN: 41450

American (AMR) AF: 0.00316 AC: 48 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67766

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00950

Asia WGS AF: 0.00174 AC: 6 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Microcephaly 5, primary, autosomal recessive (3)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.73
DANN	Benign	0.61
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115045814; hg19: chr1-197069554;